Linparza, 100 mg 56 pcs.

Olaparib is a potent inhibitor of the human poly(ADP-ribose)-polymerase (PARP) enzymes PARP-1, PARP-2 and PARP-3. Olaparib has been shown to inhibit the growth of certain tumor cell lines in vitro and tumor growth in vivo when monotherapy and in combination with conventional chemotherapy drugs.

The PARP enzymes are required for effective repair of single-stranded DNA breaks. PARP-induced repair requires that, after chromatin modification, PARP itself modifies and separates from the DNA to open access for basic excision repair enzymes to the site of the break.

When olaparib binds to the active site of the DNA-bound PARP enzyme, it prevents PARP from detaching and fixes it to the DNA, thereby blocking repair. In dividing cells, this causes the replication fork to stop at the location of the PARP-DNA complex and leads to double-stranded DNA breaks.

In normal cells, double-stranded DNA breaks are repaired by homologous recombination. In tumor cells lacking functional components of repair by homologous recombination, such as BRCA1 or BRCA2, double-stranded DNA breaks cannot be accurately and efficiently repaired by homologous recombination.

Instead, repair is carried out by alternative pathways, such as nonhomologous end joining, associated with introducing a large number of errors into the DNA, which increases genomic instability. After several replication cycles, genomic instability can reach unacceptable levels and lead to the death of tumor cells, which initially carry a high mutational load compared to normal cells.

In the absence of mutations in the BRCA1 or BRCA2 genes, DNA repair by homologous combination can be disrupted by other mechanisms, although the resulting abnormalities and their manifestations are not fully known.

The lack of a fully functional repair pathway via homologous recombination is one of the key factors determining the sensitivity of ovarian and other types of cancer cells to platinum drugs.

In in vivo models with BRCA deficiency, olaparib administered after platinum drug therapy resulted in delayed tumor progression and increased overall survival compared with platinum drug therapy alone, which correlated with the duration of olaparib maintenance therapy.

The effect on the QT interval

Multiple administration of olaparib at a dose of 300 mg 2 times daily had no clinically significant effect on myocardial repolarization (based on no effect on the QT interval).

Pharmacokinetics

Indications

Ovarian Cancer

Linparza® is indicated as monotherapy:

• Supportive monotherapy for newly diagnosed advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer of high malignancy with mutations in the BRCA gene in adult patients who have responded (complete or partial response) to first-line platinum-containing chemotherapy.
• Maintaining monotherapy of platinum-sensitive relapsed epithelial ovarian cancer, fallopian tube cancer, or primary high-grade peritoneal cancer in adult patients who have responded (complete or partial response) to platinum-containing chemotherapy.

Breast Cancer

Linparza® is indicated as monotherapy:

• Metastatic NOTR2-negative breast cancer in adult patients with germinal mutations in the BRCA gene who have previously received neoadjuvant or adjuvant chemotherapy or chemotherapy for metastatic disease.

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Active ingredient

Olaparib

Composition

1 tablet:

olaparib 100 mg;

Extrudate excipients: copovidone K28 – 230 mg, colloidal anhydrous silica – 3.33 mg.

Excipients used after the extrusion process: mannitol – 58.67 mg, colloidal anhydrous silica – 4 mg, sodium stearyl fumarate – 4 mg.

Shell composition: hypromellose 2910 (6 mPa*s) – 8.75 mg, macrogol 400 – 0.88 mg, titanium dioxide – 3.74 mg, iron oxide yellow dye – 0.64 mg.

How to take, the dosage

Linparza^® is available as 100 mg and 150 mg tablets.

The recommended dose of Linparza^® is 300 mg (2 150 mg tablets) 2 times daily, which is the daily dose of 600 mg. The 100 mg tablets are intended to be taken if a lower dose is needed.

The duration of therapy

Supportive therapy for newly diagnosed advanced ovarian cancer

Patients with newly diagnosed epithelial ovarian, fallopian tube, or primary high-grade peritoneal cancer with mutations in the BRCA gene may continue therapy for up to 2 years or until disease progression.

In the case of complete response (no radiological signs of disease), therapy should be discontinued 2 years after the start of treatment. If a partial response persists 2 years after the start of therapy, treatment may be continued beyond 2 years if the physician believes it may benefit the patient.

Platinum-sensitive relapsed ovarian cancer and metastatic HER2-negative breast cancer

Patients with platinum-sensitive recurrence of epithelial ovarian, fallopian tube, or primary peritoneal cancer, as well as patients with HER2-negative breast cancer and germinal mutations in the BRCA gene are recommended to continue therapy until disease progression.

Important dosing differences between tablets and capsules of Linparza^®

Linparza^® is also available in 50 mg capsule form. For questions about dosing of the capsules, please refer to the instructions for use of the capsules.

Linparza^® in capsule form (50 mg) should not be substituted for the same dose of Linparza^® in tablet form (100 mg and 150 mg) because of the differences in dosing and bioavailability of each form.

Dose skipping

If a dose is skipped, take the next regular dose at the usual time.

Dose adjustment

Dose adjustment for adverse reactions

To control adverse reactions, therapy may be withheld, and the dose of the medication may be reduced at a later time.

The recommended reduced dose of the drug is 250 mg (1 tablet of 150 mg and 1 tablet of 100 mg) 2 times daily (corresponding to a daily dose of 500 mg).

If further dose reduction is required, the dose is recommended to be reduced to 200 mg (2 tablets of 100 mg) 2 times daily (corresponding to a daily dose of 400 mg).

Correction of the drug dose when concomitant use with CYP3A inhibitors

The concomitant use of potent or moderate CYP3A inhibitors is not recommended; the use of alternative drugs should be considered. If concomitant use of a potent CYP3A inhibitor is necessary, reduction of the dose of Linparza ^® to 100 mg (1 tablet of 100 mg) twice daily (corresponding to a daily dose of 200 mg) is recommended.

If it is necessary to use a moderate CYP3A inhibitor concomitantly, it is recommended to decrease the dose of the drug Linparza^® to 150 mg (1 tablet of 150 mg) 2 times daily (corresponding to daily dose of 300 mg) (see sections “Drug Interactions” and “Special Indications”).

The use in special patient groups

Children

Linparza® is contraindicated in children and adolescents because the safety and effectiveness of the drug in this population has not been established.

Patients in the elderly (over 65 years)

There is no need to adjust the initial dose of the drug in elderly patients. There are limited data on the use of olaparib in patients aged 75 years and older.

In patients with renal impairment of moderate renal function (creatinine clearance of 31 to 50 ml/min) the recommended dose of Linparza® is 200 mg (2 tablets of 100 mg) 2 times daily (corresponding to a daily dose of 400 mg).

The drug Linparza^® is contraindicated in patients with severe renal dysfunction or with terminal renal failure (creatinine clearance≤30 ml/min), since the safety and pharmacokinetics of olaparib have not been studied in these patients.

In case of mild renal dysfunction (creatinine clearance between 51 and 80 ml/min), no dose adjustment is required.

Patients with hepatic impairment

Linparza^® can be used in patients with mild to moderate hepatic impairment (Child-Pugh class A or B) without dose adjustment (see section “Pharmacokinetics”). Linparza^® is contraindicated in patients with severe hepatic impairment (Childe-Pugh class C) as its safety and pharmacokinetics have not been studied in these patients.

How to use

In oral administration. The tablets should be swallowed whole without chewing, dissolving, crushing or breaking. The drug may be taken regardless of meals.

Interaction

Clinical studies of olaparib in combination with other antitumor drugs, including DNA-damaging drugs, have shown potentiation and prolongation of myelosuppressive toxicity.

The dose of Linparza® recommended for monotherapy is not appropriate for combination with other myelosuppressive antitumor drugs.

The effect of other drugs on olaparib

Powerful and moderate inhibitors of CYP3A isoenzymes

The metabolism of olaparib is primarily through cytochrome CYP3A4/5 isoenzymes. Concomitant use of olaparib with the potent CYP3A inhibitor itraconazole increased the mean Cmax of olaparib by 42% and the mean AUC by 170%.

We therefore do not recommend the combined use of itraconazole as well as other potent CYP3A inhibitors such as telithromycin, clarithromycin, protease inhibitors enhanced by ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir et al, with the drug Linparza® (see section “Special Indications”).

According to physiologically based pharmacokinetic modeling data, coadministration with moderate CYP3A isoenzyme inhibitors slows down the clearance of olaparib. Therefore, co-administration of olaparib with moderate CYP3A isoenzyme inhibitors such as Ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil, etc. is not recommended (see section “Special indications”).

In cases when concomitant use with a potent or moderate CYP3A inhibitor is required, the dose of the drug Linparza® should be reduced (see section “Dosage and administration”). In addition, grapefruit juice should not be consumed during therapy with Linparza® because it is a CYP3A inhibitor.

Powerful and moderate inducers of CYP3A isoenzymes

In co-administration of olaparib with rifamgscin, a potent inducer of CYP3A, the Cmax of olaparib was reduced by 71% and the AUC by 87%.

Because of the possibility of significant decrease of efficacy of the drug Linparza® when used together with potent CYP3A inducers such as phenytoin, rifabutin, rifampin (rifampicin), carbamazepine, nevirapine, phenobarbital, preparations of Saint John’s wort, etc, their combined use is not recommended (see section “Special Indications”).

According to physiologically based simulations of pharmacokinetics, co-administration with moderate inducers of CYP3A isoenzymes reduces the AUC of olaparib by 60%.

Hence, due to the potential for a significant decrease in efficacy of Linparza® when co-administered with moderate CYP3A inducers such as bosentan, efavirenz, etravirine, modanafil, nafcillin, etc., their co-administration is not recommended.

If a moderate CYP3A inhibitor is required, the potential decrease in the clinical effectiveness of Linparza® should be kept in mind (see section “Special Precautions”).

The effect of olaparib on other drugs

In vitro interactions mediated by CYP isoenzyme

In vitro it was shown that olaparib can both inhibit and induce CYP3A4 isoenzyme. However, data from physiologically based pharmacokinetic modeling and clinical data indicate that the resulting effect is weak inhibition of the CYP3A4 isoenzyme in vivo.

In this regard, sensitive CYP3A substrates or substrates with a narrow therapeutic range (e.g. simvastatin, cisapride, cyclosporine, ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine) should be used with Linaparza with caution. For patients who receive CYP3A substrates with a narrow therapeutic range concomitantly with olaparib, appropriate clinical monitoring is recommended.

In in vitro conditions, induction of CYP1A2 and 2B6 has been demonstrated, with the CYP2B6 isoenzyme being the most likely to be clinically significant. Therefore, concomitant use with Linparza® may decrease the exposure of substrates of these metabolic enzymes.

Interactions with drug transporter proteins

It has been shown that under in vitro conditions olaparib can inhibit OATP1B1, OST1, OST2, OATZ, MATE1 and MATE2K. The clinical significance of this phenomenon is unknown.

. However, it cannot be excluded that olaparib may increase exposure to the substrates OATP1B1 (e.g., bosentan, glibenclamide, repaglinide, statins and valsartan), OAT1 (e.g., metformin), OAT2 (e.g., serum creatinine), OAT3 (e.g., furosemide and methotrexate), MATE1 (e.g., metformin and cisplatin) and MATE2K (e.g., metformin).

In particular, caution should be exercised when prescribing olaparib concomitantly with any drug from the statin group.

Special Instructions

Hematologic toxicity

Hematologic toxicity, including clinical and laboratory signs of anemia, neutropenia, thrombocytopenia and lymphopenia, usually of mild to moderate severity (STSAE grade 1 or 2) has been reported in patients receiving olaparib.

Patients should not initiate therapy with Linparza® until they have recovered from hematologic toxicity caused by prior antitumor therapy (hemoglobin concentration, platelet count and neutrophil count should be within grade 1 STSAE severity).

It is recommended that a clinical blood count be performed prior to initiating therapy, repeated monthly for the first 12 months of therapy and periodically thereafter to monitor clinically significant changes in hematologic parameters during treatment (see section “Adverse effects”).

If a patient has severe hematologic toxicity or is dependent on frequent hemotransfusions, therapy with Linparza® should be suspended and appropriate hematologic testing performed.

If abnormal hematologic parameters persist 4 weeks after discontinuation of Linparz® , bone marrow and/or cytogenetic blood tests are recommended.

Myelodysplastic syndrome/acute myeloleukemia

The incidence of myelodysplastic syndrome/acute myeloleukemia (MDS/OML) in patients treated with Linparza® as monotherapy in clinical trials, including long-term follow-up, was less than 1.5%; most cases ended in death. All patients had predisposing factors for the development of MDS/OML.

All patients had previously received platinum-containing chemotherapy, and many had also received other DNA-damaging drugs. Most cases of MDS/OML were seen in carriers of germinal BRCA gene mutations, and some patients had a history of other primary malignancy or bone marrow dysplasia.

If the presence of MDS/OML is confirmed during therapy with Linparza®, it is recommended that Linparza® be withdrawn and the patient be given appropriate therapy.

Pneumonitis

Pneumonitis has been reported in less than 1% of patients treated with Linparza® as monotherapy in clinical trials. Reports of pneumonitis did not have a consistent clinical picture.

The identification of a causal relationship was difficult due to the presence of multiple predisposing factors (cancer and/or lung metastases, background lung disease, a history of smoking and/or prior chemotherapy and radiation therapy).

When using Linparza® in combination with other antitumor drugs there have been cases of fatal pneumonitis. If new symptoms or worsening of existing respiratory symptoms, such as dyspnea, cough, and fever, or changes on x-ray examination are noted in a patient, therapy with Linparza® should be stopped and a further investigation should be performed immediately.

If the diagnosis of pneumonitis is confirmed, treatment with Linparza® should be discontinued and appropriate therapy should be started.

Embryophyte toxicity

Owing to its mechanism of action (PARP inhibition) olaparib may cause fetal growth disorders if the drug is taken by a pregnant woman.

Preclinical studies have shown that olaparib has adverse effects on fetal survival in rats and induces severe fetal malformations at exposures below those expected in humans when the drug is used at the recommended dose of 300 mg twice daily.

The use of Linparza® during pregnancy is contraindicated. If a woman is pregnant when taking Linparza® she should be informed about the possible risk to the fetus. Women with preserved reproductive function should use effective contraception during therapy and for 1 month after the last dose of Linparza®.

Men who take Linparza® and their fertile female partners should use effective contraception during therapy and for 3 months after the last dose (see section “Use during pregnancy and breastfeeding”).

Breast-feeding period

There have been no studies on the excretion of olaparib into the breast milk of animals or women. Administration of Linparza® is contraindicated during breastfeeding and within 1 month after the last drug administration (see section “Administration during pregnancy and breastfeeding”).

Interaction with other medicinal products

The co-administration of Linparza® with potent or moderate inhibitors of cytochrome CYP3A isoenzymes is not recommended (see section “Interaction with other medicinal products”).

If the use of a potent or moderate cytochrome CYP3A isoenzyme inhibitor is necessary, the dose of the drug Linparza® should be reduced (see section “Dosage and administration”).

The co-administration of Linparza® with potent or moderate inducers of CYP3A cytochrome isoenzymes is not recommended.

If a patient who is already receiving Linparza® requires therapy with a potent or moderate CYP3A inducer, the potential for significant reduction of the clinical effect of Linparza® should be kept in mind (see section “Interaction with other medicinal products”).

Influence on the ability to drive and operate vehicles

Studies on the effect of olaparib on the ability to drive and operate vehicles have not been conducted. General weakness, fatigability and dizziness may be present during the use of Linparza® , patients with these symptoms should use caution while driving vehicles and operating machinery.

Contraindications

• High sensitivity to olaparib or any of the excipients in the drug;
• high renal dysfunction;
• high liver dysfunction (grade C on the Child-Pugh scale);
• pregnancy and breastfeeding (during therapy and within 1 month of the last drug intake);
• children and adolescents under 18 years of age (efficacy and safety not established).

Cautions
• Combined use with potent inducers or inhibitors of cytochrome CYPCA isoenzymes, moderate renal dysfunction

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Overdose

Symptoms of overdose of Linparza® are not established, there is no specific therapy. In case of overdose, general supportive measures and symptomatic therapy should be carried out.

Pregnancy use

Olaparib is contraindicated in pregnancy because of its teratogenic and genotoxic potential. Women who are partners of male patients taking Linparza® should also avoid pregnancy. No studies involving pregnant women have been conducted.

If a woman or her male partner becomes pregnant while taking Linparza®, she should be informed about the possible risk to the fetus and the possible risk of spontaneous abortion (see section “Cautionary information”).

Contraception and pregnancy detection tests

Women with preserved reproductive function should use effective contraception during therapy and for 1 month after the last dose of Linparza® (see section “Special considerations”).

A pregnancy test should be performed on all women with preserved fertility before therapy and should be repeated regularly during therapy and 1 month after the last dose of the drug.
It is not known whether olaparib or its metabolites are excreted into the seminal fluid.

Male patients should use condoms during sexual intercourse with pregnant women or women with preserved reproductive function during therapy and for 3 months after the last dose of Linparza®.

Women who are partners of male patients should also use effective contraception if they have preserved reproductive function (see section “Special Precautions”). Male patients should not be sperm donors during therapy and for 3 months after the last dose of Linparza®.

Breast-feeding

No data on the use of Linparza® during breast-feeding. There have been no studies of olaparib excretion into breast milk of animals or women. A risk to breastfed infants cannot be excluded.

Linparza® is contraindicated during breastfeeding and for 1 month after the last drug administration (see section “Contraindications”).